A. Barriers to optimal pain control. Pain is one of the most common and dreaded symptoms associated with cancer. Its prevalence ranges from 30% to 40% in those getting active therapy to nearly 90% of those with advanced cancer. Uncontrolled pain precludes a satisfactory quality of life. However, advances in pain management techniques have made it possible to control pain in most cancer patients. Barriers that exist to the achievement of optimal analgesia can be divided into patient, physician, and institutional components.

1. Patient-related barriers include

a. Reluctance to report pain (because of concerns about distracting physicians from treatment of the cancer and fears that pain means that the disease is worse)

b. Difficulty in following recommendations (health illiteracy)

c. Fear of addiction (or being thought of as an addict)

d. Worries about side effects (and the ability to manage them)

e. Fear of disease progression, injections, and a belief that pain must be accepted

2. Physician barriers include

a. Failure to appreciate the severity of pain

b. Knowledge deficit regarding specific treatment for pain (physicians largely underdose patients because of excessive concern about the dose and side effects of opioids and fear of patient addiction)

3. Institutional barriers for optimal pain management include

a. Lack of commitment to make pain treatment a priority

b. Lack of resources

c. Lack of use of instruments for pain assessment (but anyone can use a numeric pain rating scale)

B. Assessment of pain in cancer patients. Pain is a nonspecific symptom that can result from unrelated benign diseases, effects of treatment, paraneoplastic syndromes, or the direct mechanical effects of the cancer. Pain determined to result from direct mechanical effects of a cancer must be assessed in terms of whether the underlying disease can be treated to relieve the pain. To provide effective pain treatment, an appropriate differential diagnosis must be determined.

1. The following steps should be done in the assessment of cancer pain:

a. Believe the patient’s complaint.

b. Take a history of the pain, which should include the site, quality, onset, exacerbating and relieving features, associated symptoms, impact on quality of life and psychological state, and response to previous and current therapies.

c. Assess the pain as acute, chronic, intermittent, incident, or breakthrough.

d. Prioritize each complaint.

e. Assess for previous history of alcohol or drug dependence.

f. Perform medical and neurologic examinations.

g. Consider diagnostic procedures.

h. Treat and assess response to therapy.

i. Individualize therapy.

j. Communicate with the patient via pain intensity scales.

2. Patient self-assessment is the most reliable guide to both the cause of the pain and the effectiveness of pain treatment. A log should be kept to track the times that the pain is worst, the intensity of the pain, the times and doses of pain medications or other analgesic measures, and the response to these measures.

Numeric rating scales are probably the easiest for patients to use. An example is a pain scale of 0 to 10 (0 is for the absence of pain and 10 is for the most severe pain imaginable to the patient). The physician uses the information to adjust dosage and timing of analgesic medications or to change therapy.

3. Evaluation for depression is an essential part of pain management. Chronic pain leads to depression, which progressively lowers the pain threshold and creates a positive-feedback cycle of pain and depression. Solicit symptoms of depression, including loss of energy, abnormal sleep patterns, loss of appetite, loss of interest, and decreased ability for cognitive distraction. Some of these symptoms are mistaken for signs of progressive cancer.

C. Principles of pain management in cancer patients when the underlying cause cannot be treated effectively

1. Ideally, the goal of cancer pain management is complete relief of pain. Even when this is not possible, maximizing pain control improves overall functioning and quality of life.

2. Pharmacologic step management of cancer pain. The World Health Organization (WHO) has designed a three-step approach to the systemic management of pain.

Step 1: Patients with mild cancer-related pain can be treated with nonopioid analgesics. These can be combined with other adjuvant analgesics if necessary.

Step 2: Patients with moderate pain, or those who do not get analgesia with the step 1 agent, can be treated with opioids such as hydrocodone or oxycodone conjugated to acetaminophen. Tramadol, a weak opioid with effects on serotonin and norepinephrine uptake, is also a step 2 agent.

Step 3: Patients with severe pain and those who do not get relief with agents appropriate to step 2 should get an opioid designed for moderate to severe pain. This group includes morphine, hydromorphone, methadone, fentanyl, and oxycodone. Newer opioids, such as oxymorphone and its long-acting form (Opana), increase the available step 3 options. These can be combined with a nonopioid analgesic or an adjuvant agent. Sometimes it is necessary to go directly to a step 3 agent.

3. Intrathecal analgesics are often used when patients develop intolerable adverse effects to oral opioids or experience inadequate pain relief.

4. Blocks and neurosurgical procedures (see Section I.I.3)

5. Localized pharmacologic analgesics and nonpharmacologic interventions for pain, although not commonly required, are an important part of the armamentarium for pain control. These range from injections of glucocorticoid-lidocaine into isolated painful soft tissue areas to nerve blocks involving ganglia, such as the celiac or hypogastric plexus.

6. Placebos are never indicated for the treatment of cancer pain unless the patient is enrolled in a clinical trial in pain management.

7. Physical dependence and tolerance are common side effects of prolonged use of opiate analgesics in cancer patients. The development of addiction to opioid analgesics in patients with cancer pain is low. Terminology is as follows:

a. Tolerance is the need to increase the dose to maintain the same effect. Pharmacologically this is a rightward shift in the dose response curve.

b. Physical dependence is the state where continued administration is necessary to prevent the onset of withdrawal symptoms.

c. Psychological dependence describes compulsive drug-seeking behavior and overwhelming involvement with drug procurement and use.

d. Pseudoaddiction is when the patient with unrelieved pain develops what appears to be drug-seeking behavior to relieve that pain.

8. Ineffective analgesia is administered because of the barriers to optimal pain control (Section I.A), or persistent pain may mean that the underlying cancer is progressing.

9. Certain analgesics should be avoided. Analgesics with mixed agonist and antagonist properties, such as pentazocine (Talwin) or propoxyphene (Darvon), should not be used. Likewise, meperidine (Demerol) should not be used because it is not potent, and a risk exists of metabolite accumulation in the setting of renal insufficiency.

D. Nonnarcotic analgesics, particularly nonsteroidal anti-inflammatory drugs (NSAID)

1. Acetaminophen (AMP, paracetamol, Tylenol and others). As with aspirin, AMP is an antipyretic. Unlike aspirin, AMP has no anti-inflammatory or antiplatelet actions. The starting dose is 650 mg PO q.i.d. and the maximum is 4,000 mg/d.

a. Aspirin (ASA, acetylsalicylic acid) is the standard against which other NSAIDs are compared. This analgesic is significantly more effective than placebo in patients with pain from cancer. Aspirin should not be used in patients with a history of the syndrome of nasal polyps and asthma, gastritis, peptic ulcer disease, or bleeding diathesis (including severe thrombocytopenia or concomitant use of anticoagulants). Aspirin can inhibit platelet aggregation for 1 week or more.

b. Choline magnesium trisalicylate (Trilisate) is believed to have less gastrointestinal (GI) toxicity than other NSAIDs and no antiplatelet effect, but does have anti-inflammatory properties. The starting dose is 1,500 mg PO once, then 1,000 mg b.i.d. This drug is useful in patients with thrombocytopenia.

3. Cyclo-oxygenase (COX) inhibitors can be useful in the treatment of bony metastasis, paraneoplastic fever, and paraneoplastic periosteitis. They are divided into nonselective COX-1 and selective COX-2 inhibitors. COX-1 is present in most tissues, helps maintain gastric mucosa, and influences kidney and platelet function. COX-2 is induced in response to injury and is involved in the inflammatory cascade. Cox inhibitors can act synergistically with other analgesics such as opioids.

The nonselective inhibitors can cause gastric ulcers and GI bleeding as well as reversibly affect platelet function. The selective COX-2 inhibitors have relatively reduced the risk of GI toxicity and reduced antiplatelet effect associated with their use. NSAID-induced ulcer disease may be reduced by the coadministration of H₂ blockers or proton pump inhibitors such as omeprazole (Prilosec, 20 mg PO daily). Misoprostol (Cytotec), 100 µg PO q.i.d. can also ameliorate the GI side effects.

a. Nonselective NSAID that are useful orally include (among others)

(1) Ibuprofen (Advil), 200 to 800 mg q.i.d. PO

(2) Naproxen (Naprosyn), 250 to 750 mg b.i.d. PO

(3) Indomethacin (Indocin), 25 to 75 mg t.i.d. PO

b. Selective COX-2 inhibitors include

(1) Celecoxib (Celebrex), 100 to 200 mg once or twice daily PO

(2) Meloxicam (Mobic), 7.5 mg once or twice daily PO

c. Ketorolac (Toradol) is an NSAID available in IM and IV forms. The dose is 30 mg IM or IV once, then 15 mg q6h (not to exceed 5 days).

1. Corticosteroids are indicated in refractory neuropathic pain, bone pain, pain associated with capsular distension (painful hepatomegaly), duct obstruction, headache associated with central nervous system (CNS) metastasis, bowel obstruction, and ascites. The dose in these conditions is largely empiric.

2. Bisphosphonate infusion every 4 weeks is the treatment of choice for bone pain and fracture prevention from osteolytic lesions of multiple myeloma. It may also be helpful in controlling bone pain in up to 25% of patients with breast cancer or prostate cancer. Either pamidronate (Aredia, 90 mg IV over 3 hours) or zoledronate (Zometa, 4 mg IV over 15 minutes) can be used.

a. Benzodiazepines. Anxious or agitated patients often perceive anxiety as a painful sensation. Diazepam (Valium), alprazolam (Xanax), or lorazepam (Ativan) may be used if narcotic analgesics alone are not effective. These drugs should be avoided in patients with dementia and may produce paradoxical agitated, confusional states in some patients. They may interact with opioids to produce increased somnolence and thus they are looked for first when patients on opioids already develop “opioid” adverse effects, such as increased sedation.

b. Antihistamines, such as hydroxyzine (Atarax, Marax), 25 to 100 mg PO q.i.d., may be useful in the anxious patient as a mild anxiolytic agent with sedating, analgesic, antipruritic, and antiemetic properties.

c. Pain can be associated with increased delirium. Patients with dementia can become agitated and confused when they develop pain. These patients often benefit from a regimen of haloperidol (Haldol), 1 to 3 mg/d, with analgesics. This drug can cause extrapyramidal symptoms, torticollis, and swallowing problems. Haloperidol is contraindicated in patients with Parkinson disease. Diphenhydramine (Benadryl) and benztropine mesylate (Cogentin) rapidly reverse extrapyramidal symptoms. Another option in the demented patient who has delirium is to use the newer atypical antipsychotics, such a quetiapine (Seroquel), which have a more favorable side effect profile, at least when it comes to extrapyramidal symptoms and are very useful in patients with Parkinson disease.

F. Neuropathic pain syndromes, particularly if the pain is lancinating or burning, can often be treated with anticonvulsant drugs alone or in combination with tricyclic antidepressants. These drug combinations are often effective in treatment of peripheral neuralgias, postherpetic neuralgia, and tic douloureux. Gabapentin is considered to be the first-line agent in the treatment of neuropathic pain. Typical doses are as follows:

1. Antiseizure drugs used for neuropathic pain

a. Gabapentin (Neurontin), starting dose is 300 mg PO at bedtime (h.s.). The maximal dose is 3,600 mg/d/with q.i.d. dosing.

b. Phenytoin (Dilantin), starting dose is 100 mg b.i.d.; titrate upward by 100-mg increments every 3 to 7 days and monitor for side effects.

c. Carbamazepine (Tegretol), starting dose is 100 mg b.i.d.; titrate to toxic level by 100-mg increments every 3 to 7 days.

d. Lamotrigine (Lamictal), 25 mg PO h.s.; increase dose q3d

e. Topiramate (Topamax), 25 mg PO h.s.; increase dose q3d

f. Valproic Acid (Depakote), 200 to 400 mg PO b.i.d. or t.i.d.

g. Antidepressant drugs (see Section I.F.2)

2. Antidepressants are useful adjuvant analgesics that provide relief at doses below that needed to treat depression. Trials suggesting efficacy have been done in patients with postherpetic neuralgia or diabetic neuropathy. There are few clear studies indicating efficacy in the cancer patient population.

a. Tricyclic antidepressants, which may have lost favor to gabapentin as first-line agents, include amitriptyline (Elavil), desipramine (Norpramin), nortriptyline (Pamelor), doxepin (Sinequan), and imipramine (Tofranil). These are started at 10 to 25 mg h.s. and titrated upward at 10- to 25-mg increments every 5 to 7 days.

b. Selective serotonin reuptake inhibitors (SSRIs) include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), citalopram (Celexa), and fluvoxamine (Luvox). These drugs have performed inconsistently in neuropathic pain trials.

c. Other antidepressants include venlafaxine (Effexor), bupropion (Wellbutrin), trazodone (Desyrel), nefazodone (Serzone), and mirtazapine (Remeron). Clinical experience suggests that these agents can be useful, but no controlled clinical trials have established their utility in the treatment of neuropathic pain.

3. α-Adrenergic agonists, such as tizanidine (Zanaflex, 2 mg PO h.s.), may be useful in refractory neuropathic pain but this is based on clinical experience not controlled trials. These agents are most commonly used intrathecally, along with opioids and local anesthetics.

a. IV lidocaine. Controlled trials suggest that lidocaine is effective in neuropathy associated with diabetes. Response occurs at sub-antiarrhythmic doses but lasts only a few hours. Response to IV lidocaine may be predictive of a subsequent response to mexiletine.

b. Mexiletine (Mexitil) has been found effective in patients with diabetic neuropathy on the basis of controlled clinical trials. The starting dose is 50 mg t.i.d. PO (taken with meals) with titration upward every 5 to 7 days.

a. Lidocaine patch, 5% (Lidoderm). Controlled clinical trials showed efficacy in postherpetic neuralgia. Its use in other conditions is based on anecdotal data. The dose is up to three patches topically (12 hours on and 12 hours off). There are no clinically relevant serum levels.

b. Topical capsaicin (Zostrix) depletes substance P and may act as a counterirritant. Results in trials are mixed for peripheral neuropathy and pain may actually worsen. It is not recommended.

c. Topical opioids are often used for painful ulcerations. Methadone and morphine can be compounded into topical preparations.

G. Opioids produce their analgesic effect through the interaction with specific opioid receptors. The only significant differences among the various opioids are duration of action and the dose needed to produce the same analgesic effect.

The best agents are the pure agonists. Agonists or antagonists, such as pentazocine (Talwin) or propoxyphene (Darvon), are not effective and should not
be used. Meperidine likewise should not be used because it is not potent and its metabolites accumulate in the setting of renal insufficiency. Methadone is being used more often because research has suggested that it works on other receptors involved in pain perception.

No “ceiling” to opioid doses exists. Doses can be escalated to provide analgesia as long as there are no unacceptable toxicities. Ineffectiveness observed while using opioids usually indicates underdosing; the analgesic effect and the duration of that effect increase as the dose is increased. Ineffectiveness may also reflect progression of the underlying disease, but this will also respond to a dose increment.

1. Opioids for mild to moderate pain: short-acting opioids (WHO step 2; there are no step 1 opioids)

a. Codeine phosphate: 60 mg q3—4h PO. Also available as Tylenol #2 (15 mg codeine with AMP), Tylenol #3 (30 mg codeine with AMP), and Tylenol #4 (60 mg codeine with AMP). Do not exceed 4 g/d of AMP. Codeine is rarely used for analgesia as it is especially susceptible to producing constipation. Codeine is one-eighth as potent as morphine.

b. Hydrocodone bitartrate (with ASA or AMP; Lorcet, Lortab, Vicodin): 10 mg q3-4h PO. Hydrocodone is equivalent to morphine on a milligram per milligram basis. It is not available as a stand-alone opioid.

c. Oxycodone hydrochloride (Roxicodone as single agent or in combination with AMP or ASA as Percocet, Percodan, Tylox): 5 to 10 mg q3-4h PO.

d. Tramadol (Ultram or Ultracet [with AMP]). Maximum dose for cancer pain is 300 mg/d. The immediate release form is dosed q6h; the extended release form is dosed q12h.

2. Opioids for moderate to severe pain. Short-acting opioids (WHO steps 2 and 3). Oral immediate release opioids generally have an onset of action of approximately 1 hour and their duration of effect is approximately 4 hours.

a. Morphine sulfate (MS), immediate release, is the standard against which all other analgesics are measured. The starting dose of MS in the opioid-naive patient is 0.5 to 1 mg q3-4h IV or 15 to 30 mg q3-4h PO; it can be given more frequently for acute pain crises. MS is available as

(1) Tablets and capsules (MSIR, immediate release MS): 15 and 30 mg

(2) Elixirs (Roxanol): 10 mg/5 mL and 20 mg/mL

(3) Rectal suppositories (RMS): 1, 5, 20, and 30 mg

(4) Injectable: 0.5, 1, 10, and 25 mg/mL concentrations

b. Hydromorphone (Dilaudid). Duration of action is 4 hours but can be as short as 3 hours. Available as

(1) Tablets: 1, 2, 3, 4, and 8 mg

(2) Elixir: 5 mg/5 mL

(3) Rectal suppository: 3 mg

(4) Injectables: 1-, 2-, 3-, 4-, and 10-mg/mL concentrations

c. Oxycodone hydrochloride: Considered to be both a step 2 and a step 3 agent. Not available in IV form. Available as:

(1) OxyIR, Roxicodone: 5-mg tablets and capsules

(2) Oxyfast: 20-mg/mL elixir

3. Long-acting opioids are usually started after dose titration (achievement of pain relief with short-acting opioids). Analgesic onset is in 3 to 4 hours and lasts for 12 hours. No advantage to q8h dosing, but it is often done. To derive the long-acting opioid dose, divide the total 24-hour immediate-release dose by 2. Kadian is the only long-acting opioid that can be crushed, sprinkled, and put in a feeding tube.

a. Sustained release morphine: Available as

(1) MS Contin: 15-, 30-, 60-, 100-, and 200-mg tablets

(2) Oramorph SR: 30-, 60-, and 100-mg tablets

(3) Kadian: 20-, 50-, and 100-mg capsules

b. Sustained release oxycodone is available as OxyContin in 10-, 20-, 40-, and 80-mg tablets

c. Fentanyl (Duragesic) transdermal patches: Available at delivery rates of 25, 50, 75, and 100 µg/h. Therapeutic levels are not reached for 13 to 24 hours. Patches are changed q72h; some patients need the patch changed q48h. The recommended upward dose titration interval is q72h. A 100-µg patch is equivalent to morphine given IV at 4 mg/h. Another way to convert fentanyl to morphine and vice versa is to convert 2 mg of oral morphine for every 1 µg of fentanyl. Oral transmucosal fentanyl citrate (OTFC) is available in the form of fentanyl lollipops. They have a rapid onset of action (minutes) and have been shown to be superior to morphine for “incidental pain” (see below).

d. Methadone is useful for neuropathic or severe pain. It is also useful when opioids are required in the setting of renal failure. The N-methyl-d-aspartate (NMDA) blocking ability of the drug reverses opioid tolerance. Prospective studies have shown that currently available equianalgesic dosing tables are not accurate when switching from morphine to methadone. The dosing interval should not be less than q8h. The dose may be as little as 5% to 10% of the MS dose, especially in patients on chronic MS therapy.

e. Oxymorphone. Originally used as rectal form (Numorphan suppository), this drug is now available in oral form. The immediate release form is unique, in that it has a half-life of approximately 6 hours. A long-acting form is available (Opana). The drug is slightly more potent than morphine (1.2 times).

a. GI effects include constipation, nausea, and vomiting. Define a prophylactic regimen for constipation and for nausea when the first opioid prescription is written.

(1) Constipation is the most common adverse effect of opioids. Constipation is not related to dose and can occur with small doses of opioids. It is caused by the opioid effect on motility, as well as decreased pancreatic, biliary, gastric, and intestinal secretions. Tolerance to this side effect usually does not occur (see Section IV.A.5).

(2) Nausea and vomiting caused by opioids is owing to stimulation of the chemoreceptor trigger zone. Thus, antiemetics with antidopaminergic properties are indicated. Agents such as prochlorperazine (Compazine), metoclopramide (Reglan), and haloperidol (Haldol) are good choices.

b. CNS side effects. Morphine-3-glucuronide is the morphine metabolite implicated in the development of CNS toxicity. Other manifestations of CNS toxicity include sedation, hallucinations, delirium, and myoclonus.

(1) Sedation is more common in the opioid naive patient. It rarely lasts more than 48 to 72 hours. If persistent, methylphenidate, 5 mg at 8 AM and at noon, or modafinil 200 mg/d may be useful.

(2) Myoclonus (spontaneous jerking movements) can occur in up to 45% of patients. This is an adverse effect seen with chronic opioid use. Treatment options include opioid dose reduction if pain is well
controlled, opioid rotation if pain is poorly controlled, or adding clonazepam (Klonopin, 0.5 to 1 mg) or diazepam (Valium, 2 mg) PO q12h.

c. Respiratory depression is unusual and usually only occurs in patients who are either having rapid dose escalation or are in renal failure (due to accumulation of morphine-6-glucuronide). Respiratory depression is not common because morphine does not have good bioavailability and pain is an antidote to respiratory depression. Respiratory depression can occur when pain is rapidly reduced, such as after a nerve block. It can also occur when MS is given with other CNS depressants. Treatment is by dose reduction, such as stopping the infusion for 2 hours and then restarting at half the dose, or holding one or two doses of opioids and then restarting at a lower dose if possible. Naloxone is rarely necessary.

(1) Noncardiogenic pulmonary edema occurs with rapid dose escalation and may be related to capillary permeability changes secondary to opioid release of histamine.

(2) Xerostomia is common with concomitant use of antidepressants and anticholinergic agents. Treatment includes sodium bicarbonate rinses or pilocarpine.

(3) Urinary retention is caused by the anticholinergic effects of opioids.

(4) SIADH (syndrome of inappropriate antidiuretic hormone) can be caused by opioids.

(5) Endocrine: hypothyroidism and hypercalcemia potentiate the CNS effects of opioids.

(6) Dermatologic: pruritus is more commonly seen with intrathecal opioids.

a. Potentiators of MS effect generally work by interfering with morphine metabolism. These agents include H₂ blockers, antidepressants, phenothiazines, and antianxiety agents.

b. Agents that decrease MS effect generally induce the metabolism of morphine. These agents include phenytoin, barbiturates, and rifampin.

c. MS effect on other agents. Morphine can increase gabapentin levels and reduce ciprofloxacin levels.

6. Management of narcotic withdrawal. The intensity of withdrawal symptoms is usually proportional to the duration of physical dependence. Symptoms develop within 2 to 48 hours after the last dose and usually peak at 72 hours. Opioid withdrawal is less life threatening and dangerous than withdrawal from other classes of controlled drugs. Reassurance, education, and perhaps mild sedatives may be all that is required for patients who develop physical dependence during hospitalization and who are not going to continue on the drugs. Small doses of clonidine, 0.05 to 0.1 mg PO t.i.d. (or weekly skin patches), may reduce symptoms of withdrawal, especially tremors, hypertension, anxiety, and fevers.

1. Opioid dosage. There is no maximum dose or ceiling to MS or other opioids. As the dose is increased, analgesic effects increase. Increments in dosing are always balanced by monitoring for side effects. Once stable drug levels are achieved with immediate-release dosing, the patient can be switched to a long-acting agent. Rescue doses for breakthrough pain with immediate-release agents are made available as needed (p.r.n.). With elderly patients, “go low and go slow,” taking into account age-related sensitivity to opioids as well as age-related reductions in renal function.

a. Dose finding for oral opioids. The oral route is preferred because oral opioids can control pain in patients with advanced cancer 80% to 90% of the time. Doses are given regularly (“around the clock” [ATC]) and supplemental medications are provided p.r.n.

In the opioid naive patient, the initial dose of MS can be from 5 to 30 mg depending on the severity of pain. This dose is started at q4h. The p.r.n. dose is approximately 50% of the q4h dose and is provided once during the 4-hour dosing interval. The optimal dose is one that relieves the patient’s pain (to <4 on a 10-point scale) without causing side effects. In the elderly patient, it is always best to “go low” and “go slow.” This means lower starting doses and increased dosing intervals.

Once the optimal dose is found, the total opioid amount is calculated and then divided by 2 to yield the q12h, long-acting dose. The q2-4h p.r.n. dose is approximately 10% to 20% of the total 24-hour dose.

b. Dose finding for parenteral agents. In the opioid naive patient with severe pain, initial MS doses of 2 to 4 mg IV or SQ can be given every 15 minutes as necessary to control pain. When pain is controlled, the dose given over a 2- to 4-hour interval becomes the q4h dose and the p.r.n. dose (50% of the ATC dose) is given q1—2h.

c. Need for frequent p.r.n. doses. Patients needing more than four p.r.n. opioid doses per day most likely need an increase in the ATC dose. The ATC dose can be increased by 25% to 50% and adjustments of the p.r.n. dose can be made.

d. Incident pain. Pain with turning, bathing, and transporting can be managed with p.r.n. doses or more generous p.r.n. doses at the time the patient is likely to experience the incident pain.

e. Equianalgesic tables represent rough guidelines that are based on single-dose studies in otherwise healthy patients. The potency ratio of oral MS to oral hydromorphone is 5:1 (5 mg of MS is equivalent to 1 mg of hydromorphone orally). The potency ratio for IV or SQ MS to hydromorphone is 7:1 (7 mg of MS is equivalent to 1 mg of hydromorphone IV or SQ). Oxycodone potency ranges from 1:1 to 1.5:1 compared with MS. Equianalgesic tables are not useful when converting from other step 3 opioids to methadone.

2. Subcutaneous opioids are reserved for those who cannot use the oral route for pain administration or who need rapid onset of analgesia. SQ dosing is identical to IV dosing. The limiting feature of this route is the infusion rate; in general, the SQ route can absorb up to 3 mg/h; with larger volumes, hyaluronidase (Wydase) can be given. The shoulder, abdomen, and thigh are ideal sites for infusion.

3. Pumps for patient-controlled analgesia (PCA) are occasionally useful for cancer patients. Begin with a 2- to 5-mg dose of MS with a delay interval of 10 minutes (“lockout”); the patient can thus receive this dose up to six times an hour. The amount given over 4 hours is determined and converted to an hourly dose. The new, every 10 minute demand dose becomes 50% of the hourly dose. For patients already on MS, the same method is used except that the 24-hour dose is converted to an hourly dose and then a new demand dose can be formulated.

4. Intravenous opioids are reserved for patients who cannot be given opioids by the oral route. It is also ideal for rapid titration of doses. Dosing is based on current analgesic requirements. The usual conversion from oral MS to SQ or IV MS is to divide the total oral requirement by 3 with this
representing the total IV dose. This amount can be divided by 24 to give hourly rates.

5. Epidural and intrathecal anesthesia are considered when oral and parenteral routes have proven ineffective and/or there is excessive toxicity associated with opioid use.

a. Epidural analgesia. A catheter is placed close to the involved dermatome. The type of delivery system depends on prognosis of the patient. Tumor invasion of the spine is not a contraindication, because most tumors involve the body of the vertebra and not the spinous process. To calculate the epidural dose from an oral dose, divide the total 24-hour oral dose by 10. To calculate the epidural dose from an SQ dose, divide the total 24 hour SQ dose by 5. Analgesia can be improved when combined with bupivacaine (Marcaine) or clonidine. The addition of these agents is indicated for neuropathic pain, dysesthetic pain, midline pain below the umbilicus, or pain involving the sacral plexus.

b. Intrathecal analgesia has more effective pain control, uses less opioid, and has less incidence of catheter occlusion than the epidural route. Doses for intrathecal administration are 10% of the epidural doses.

a. Rectal administration can also be used if the oral route is not available. The oral-rectal potency ratio is 1:1.

b. Sublingual and buccal administration can be used if the oral route is not available. Ideal agents for this route are the more lipophilic opioids such as fentanyl (Actiq) lollipops and methadone. These agents have a greater Buccal or sublingual bioavailability than MS. The buccal—oral potency ratio is 1:1.

c. Topical opioids have been used for painful ulcerative lesions, cutaneous pain from tumor infiltration, and oral mucositis. It is available in a 1 mg/mL gel vehicle.

1. Psychological methods of pain control. Behavioral modification, although not generally effective for moderate to severe chronic cancer pain, may be helpful for mild pain. Operant conditioning, hypnosis, guided imagery, and biofeedback are techniques that can be helpful for chronic mild pain, such as postoperative chest wall pain. Cognitive distraction is a useful adjunct for mild pain. These techniques can help patients restore self-control and act in a way that participates in their own care.

2. Physical methods of pain control, such as hot or cold packs for muscle and joint pain, various types of massage therapy, and exercise programs, may be helpful additions to drug therapy in patients with mild to moderate chronic pain syndromes, but are generally ineffective in treatment of severe cancer pain.

Transcutaneous electrical nerve stimulation (TENS) has demonstrated efficacy in the treatment of malignant disease, but the problems encountered were waning effect and sudden termination of effect. The results of clinical trials on acupuncture have been conflicting; retrospective data suggest that any efficacy of acupuncture for cancer pain is short lived.

3. Neuroablative procedures are considered when standard pain management methods and intraspinal analgesia have failed. These procedures are not for patients who have a short life expectancy or are in poor physical condition.

a. Unilateral chordotomy is the most effective neuroablative procedure and is particularly useful for patients with unilateral cancer pain below the shoulder. Radiofrequency lesions to spinothalamic tracts of the spinal cord are generally placed at the C-1 to C-2 level.

Contralateral loss of superficial, deep, and visceral pain is produced in >75% of patients treated with percutaneous chordotomy. The duration of analgesia is limited to only a few months; incapacitating dysesthesia may develop after several months. In experienced hands, unilateral chordotomy is associated with low morbidity and mortality and minimal incidence of motor weakness or loss of bladder function. Sleep apnea, fecal and urinary incontinence, loss of orgasm, and muscle weakness, on the other hand, frequently complicate bilateral chordotomy.

b. Nerve blocks may be useful in patients with pain restricted to a single somatic nerve or adjacent nerves (e.g., postthoracotomy pain may be relieved by subcostal blocks). Short-acting local anesthetics are initially used to determine the location for a permanent procedure.

c. Celiac plexus nerve block is effective in up to 85% of patients for treating upper abdominal visceral pain, particularly from cancers of the pancreas or stomach. The procedure is often accomplished with needle placement under CT or fluoroscopic guidance. It can also be performed endoscopically or at the time of laparotomy. Pretreatment hydration and postoperative observation for 4 to 6 hours (with fluid replacement as necessary) can prevent transient hypotension from this procedure.

d. Lumbar sympathetic blockade can be attempted for pelvic visceral pain. This procedure affects sphincter tone or lower extremity strength uncommonly.

e. Dorsal root entry zone lesions involve the destruction of dorsal horn neurons. It has been used to treat nonmalignant conditions such as brachial plexus avulsions, postparaplegic and postquadriplegic pain, and postamputation pain. Postherpetic neuralgia also responds to this procedure. Its usefulness in cancer pain needs to be studied further.

It is performed under general anesthesia. Proper placement of the lesion (in the cord) is important and can be difficult. Poor performance status, bleeding diathesis, infection, and poor cardiopulmonary reserve are contraindications to the procedure.

f. Intracranial procedures, such as medullary or pontine tractotomy, thalamotomy, cingulotomy, and hypophysectomy, are rarely performed.

A. Stomatitis from chemotherapy can develop 2 to 10 days after treatment with many cytotoxic agents and during RT to the head or neck. Resolution of symptoms usually occurs 2 to 3 weeks after completion of therapy but may persist longer. Sucking on ice chips or popsicles during the short infusion of certain cytotoxic agents (e.g., methotrexate, 5-fluorouracil) or taking oral glutamine preparations may prevent the development of stomatitis.

1. Aggravating factors include poor oral hygiene (gingivitis, poorly maintained dentures), xerostomia, age- or RT-related mucous membrane atrophy, and aerobic or anaerobic bacterial infections. Infection with Candida sp. or herpesvirus can complicate or be confused with chemotherapeutic stomatitis; the index of suspicion for the infections is increased in patients with acquired immunodeficiency syndrome (AIDS) and in those taking high-dose or long-term glucocorticoids.

2. Symptoms and signs. Stomatitis is usually first noted by the patient as sensitivity to citrus juice, hot food, or spicy food. Erythema and then aphthous ulcers develop. In severe cases, lesions progress to extensive ulceration and sloughing of the oral mucosa. Candida albicans or herpesvirus infection can
have a similar appearance and must be considered if the mouth lesions are longer lasting or recognized by their characteristic appearance.

3. Management of stomatitis. The following measures may relieve symptoms:

a. Avoid foods that trigger the pain

b. Abstain from alcohol

c. Suck on popsicles and cold beverages

d. Frequently rinse the mouth with solutions of saline or baking soda

e. Swish and expectorate certain commercial suspensions

(1) Ulcerease: glycerin, sodium bicarbonate, and sodium borate

(2) BAX: lidocaine, diphenhydramine, sorbitol, and Mylanta

(3) Stomafate: sucralfate, Benylin syrup, and Maalox